DESCRIPTION (adapted from the applicant's description): Heat and other stresses including exposure to noxious chemicals stimulate transcription of a group of genes encoding so-called heat shock or stress proteins (Hsps), many of which are molecular chaperones. Prior activation of this stress response makes cells, tissues, and organs more resistant to stress, and blocking this response increases susceptibility to stress. Activation of the stress response can prevent or mitigate ischemia and reperfusion injury and the toxicity of chemotherapeutic agents and inflammatory responses, and can enhance the responsiveness of the immune system. The heat shock transcription factor HSF1 is responsible for stress-induced gene activation in vertebrate cells. In unstressed cells, HSF1 resides in the cytoplasm in a complex with Hsp90 and is incapable of binding to DNA. When cells encounter stress, the rate of protein unfolding increases dramatically and the accumulating nonnative proteins compete with HSF1 for binding to Hsp90. Upon release from Hsp90, HSF1 rapidly forms a homotrimeric complex with DNA-binding activity and is translocated to the nucleus. Following trimerization, HSF1 is converted to a transcriptionally active form in a reaction that may be mediated by stress-regulated phosphorylation of specific serine and/or threonine residues in HSF1. After a stressful event, active HSF1 is recycled. The goal of this research is to discover the mechanisms for converting trimeric HSF1 to its transcriptionally active form and for subsequently deactivating HSF1 and returning it to its non-trimeric form. Mechanistic knowledge from this work will be applied to systematic studies aimed at elucidating the basis for defects in stress responses in aging cells and cells expressing prions.